Selumetinib Gets Breakthrough Designation for Neurofibromatosis Type 1


The MEK 1/2 inhibitor was previously granted an orphan drug designation by the FDA in February 2018 and resulted in partial responses in 72% of patients in the phase 2 SPRINT trial.

Dr Roy Baynes

Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories

Roy Baynes, MD, PhD

The FDA has granted a breakthrough therapy designation to AstraZeneca’s MAPK/ERK kinase (MEK) 1/2 inhibitor for the treatment of pediatric patients who are 3 years of age and older with neurofibromatosis type 1 (NF1) symptomatic and/or progressive, inoperable plexiform neurofibromas (PN).1

Patients with the rare and incurable genetic condition currently have limited treatment options that often fall into oncologist’s hands. AstraZeneca and Merck Sharp & Dohme Corp (MSD) entered a co-development and co-commercialization agreement for selumetinib in 2017. It is currently being assessed as a monotherapy as well as in combination with other treatments and was previously granted an orphan drug designation by the FDA in February 2018.

“This new designation validates our ongoing development of selumetinib. As a result of this, selumetinib has the potential to receive expedited regulatory review and we hope to bring this medicine to patients as soon as possible,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, in a statement.

The agency granted the therapy its breakthrough designation based on data from the phase 2 SPRINT clinical trial, which assessed selumetinib in 50 pediatric patients with inoperable NF1-related PN. The mean age of patients was 10.2 years (range, 3.5 to 17.4). The results of the study were presented in 2018 by the National Cancer Institute (NCI) at the American Society of Clinical Oncology (ASCO) Annual Meeting.2

SPRINT findings showed that the investigational agent induced partial responses in 72% (n = 36) of the pediatric patients enrolled in the study. Additionally, 24% (n = 12) of the cohort reported stable disease. Two patients were not re-staged, and 32 of the partial responses were confirmed upon consecutive re-staging scans after 4 months.

As well, selumetinib significantly improved both parent- and child-reported pain intensity and interference scores (P <.01), as well as strength and range of motion of the impacted muscle groups and joints (P <.01).

Patients in the study were given 25 mg/m2/dose of selumetinib twice daily continuously in 28-day cycles until progression of their disease or intolerable toxicity. Patients received treatment for a median of 19.5 cycles (range, 0 to 29). The primary end point was the complete and partial response rate as measured by volumetric MRI, while secondary end points consisted of the impact of treatment on pain and quality of life, safety, and pharmacodynamics.

At baseline, 21 patients had disease progression, disfigurement was observed in 44, motor function difficulties were apparent in 33, and 28 reported experiencing pain. Additional plexiform neurofibroma-related issues included airway issues in 16 patients, vision troubles in 10, bowel/bladder dysfunction in 10, and other morbidities in 9 patients.

The most common adverse events (AEs) observed were gastrointestinal toxicities, creatine phosphokinase increased, rash, and paronychia. The most frequent toxicities were nausea/vomiting, diarrhea, asymptomatic creatine kinase increase, acneiform rash, and paronychia. Selumetinib dose was reduced in 12 patients, 5 of which were removed from treatment due to grade 3/4 AEs that may have been due to treatment.

“Selumetinib shows promise in the treatment of NF1-related plexiform neurofibromas, a rare and debilitating disease with no approved medications to date,” José Baselga, MD, executive vice president, research and development, oncology, AstraZeneca, said in a statement. “The Breakthrough Therapy Designation acknowledges the significant unmet need of these patients and the potential benefit of selumetinib in this setting.”

The NF1 gene produces the neurofibromin protein, which negatively regulates the RAS/MAPK pathway to control cell growth, differentiation, and survival. When mutated, NF1 can cause dysregulations in RAS/RAF/MEK/ERK signaling, so the goal of selumetinib is to inhibit the MEK enzyme in this pathway with the intention of inhibiting tumor growth.


1. Selumetinib granted US Breakthrough Therapy Designation in neurofibromatosis type 1 [press release]. Kenilworth, NJ: AstraZeneca; Published April 1, 2019. Accessed April 2, 2019.

2. Gross AM, Wolters P, Baldwin A, et al. SPRINT: Phase II study of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN). J Clin Oncol. 2018 (suppl; abstr 10503). doi: 10.1200/JCO.2018.36.15_suppl.10503.

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